NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

• Published in: Molecular oncology Vol. 11; no. 4; pp. 438 - 451
• Main Authors: Cirenajwis, Helena, Lauss, Martin, Ekedahl, Henrik, Törngren, Therese, Kvist, Anders, Saal, Lao H., Olsson, Håkan, Staaf, Johan, Carneiro, Ana, Ingvar, Christian, Harbst, Katja, Hayward, Nicholas K., Jönsson, Göran
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.04.2017; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; Automobile industry; BRAF; Cancer and Oncology; Cancer och onkologi; Clinical Medicine; Cohort Studies; Female; Gene mutations; Genes; Genome, Human; Humans; Klinisk medicin; Male; MAP Kinase Signaling System - genetics; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Medicine, Experimental; Melanoma; Melanoma - enzymology; Melanoma - genetics; Melanoma - pathology; Metastasis; Middle Aged; Mutation - genetics; Neurofibromin 1 - genetics; NF1; NRAS; Survival Analysis; Sweden; Japan; NF1; melanoma; NRAS; BRAF
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12050

In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group. Melanoma is stratified based on somatic mutations in BRAF, NRAS, or NF1 genes. However, the clinical significance of this classification is unknown. Here, Cirenajwis et al. in silico combined in‐house mutation data with data from three published studies. Collectively, the NF1‐mutated subtype had a higher mutational burden, was enriched for male patients and older patients as well as an increased risk of death from melanoma. This highlights the need for improved characterization of this group.